A cyanide-free synthesis of nitriles exploiting flow chemistry

Abstract

A continuous flow process for the synthesis of aryl nitriles in a cyanide-free manner is reported. Using a simple setup and mild conditions, TosMIC (p-tosylmethyl isocyanide) is used as a readily available precursor to convert ketones into nitriles via the van Leusen reaction. The resulting continuous process is fast (1.5 minutes residence time) and both the scalability (up to 8.8 g h⁻¹) and reproducibility of this approach has been demonstrated for a variety of nitrile products. Through these studies, 4-tosyloxazole was isolated as a side-product that aids in understanding the mechanistic pathways of this transformation. Overall, this efficient flow method provides for a straightforward flow synthesis of nitrile-containing building blocks in high yields and with an improved safety profile.